Project Summary/Abstract This research will develop wearable sensors analogous to the pulse oximeter, but to monitor heparin anticoagulation therapy and other drugs with a narrow therapeutic window. This work is exceptionally innovative and completely distinct from other work on therapeutic drug monitoring because it is sample-free, acoustics-based, non-invasive, and real-time. This approach is also the only design to measure the heparin/anti-thrombin complex in contrast to existing surrogate methods that simply measure clotting time. Although applicable to multiple drugs, we will focus on heparin because it is a cornerstone (500M doses/year) of surgical and cardiovascular medicine. Heparin has variable molecular weight, activity, biodistribution, and pharmacokinetics resulting in a narrow therapeutic window causing heparin to be the second most common medication error. The current standard for heparin monitoring is the activated partial thromboplastin time (aPTT); however, this in vitro diagnostic tool suffers from long turnaround times, a variable reference range, and poor correlation to outcome. To solve this, I will develop novel wearable ultrasound-based sensors. In particular, I will use photoacoustic imaging?a hybrid approach that uses incident light pulses to trigger an acoustic signal. Its spectral nature, intense contrast, and high frame rate facilitates real-time, multiplexed, and high sensitivity measurements. These are ideal features for therapeutic drug monitoring. First, we will synthesize novel sensing molecules. We will then integrate these chemical sensors into wearable devices that will interact with ultrasound transducers to quantitate coagulation without venipuncture. In the final phases of the program, we will validate this approach with animal models and expand this to other drugs such as digoxin and phenytoin as well as multiplexed sensors. Rather than injecting a contrast agent and hoping it goes to the site of disease in vivo or drawing blood and processing it in vitro, this work will immobilize a sensor in situ for constant feedback on anticoagulation therapy. The confluence of imaging technology, wearable technology, and chemical technology that I offer here will truly revolutionize the incredibly common practice of heparin therapy?patients will no longer be subjected to invasive sampling and will avoid dangerous overdoses and underdoses. Doctors and nurses will have instantaneous feedback on their patients and smart infusion pumps will carefully and automatically titrate drug dosages. Long term, this work will translate into significant cost savings for insurers and providers.